کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
2485920 | 1114370 | 2010 | 10 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Effect of altered AGP plasma binding on heart rate changes by S(â)âpropranolol in rats using mechanismâbased estimations of in vivo receptor affinity (KB,vivo)
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موضوعات مرتبط
علوم پزشکی و سلامت
داروسازی، سم شناسی و علوم دارویی
اکتشاف دارویی
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چکیده انگلیسی
In contrast to the impact of plasma protein binding on pharmacokinetics, no quantitative in vivo information is available on its impact on pharmacodynamics. The pharmacokinetic-pharmacodynamic relationship of the model drug S(â)âpropranolol was evaluated using mechanismâbased estimations of in vivo receptor affinity (KB,vivo), under conditions of altered plasma protein binding resulting from different levels of alphaâ1âacid glycoprotein (AGP). Male Wistar Kyoto rats with isoprenalineâinduced tachycardia received an intravenous infusion of S(â)âpropranolol, on postsurgery day 2 (nâ=â7) and day 7 (nâ=â8) with elevated and normal plasma protein binding, respectively. Serial blood samples were taken in parallel to heart rate measurements. AGP concentrations at 2 and 7 days postsurgery were 708â±â274 and 176â±â111âµg/mL (meanâ±âSE), respectively. Using nonlinear mixed effects modeling, AGP concentration was a covariate for intercompartmental clearance for the third compartment of the pharmacokinetic model of S(â)âpropranolol. Individual values of AGP concentrations ranged between 110 and 1150âµg/mL, and were associated with KB,vivo values of S(â)âpropranolol from 7.0 to 30ânM. Using the KB,vivo for S(â)âpropranolol with correction for average values for normal and elevated plasma protein binding, nearly identical values were found. This confirms, strictly quantitative, earlier indications that plasma protein binding restricts the pharmacodynamics of S(â)âpropranolol. © 2009 WileyâLiss, Inc. and the American Pharmacists Association J Pharm Sci 99: 2511-2520, 2010
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Journal of Pharmaceutical Sciences - Volume 99, Issue 5, May 2010, Pages 2511-2520
Journal: Journal of Pharmaceutical Sciences - Volume 99, Issue 5, May 2010, Pages 2511-2520
نویسندگان
T.J. van Steeg, E.H.J. Krekels, J. Freijer, M. Danhof, E.C.M. de Lange,